title: Induction of autophagy promotes differentiation of glioma-initiating cells and their radiosensitivity.
abstract: Glioblastoma (GBM) is a highly aggressive brain tumor characterized by increased proliferation and resistance to chemotherapy and radiotherapy. Recently, the identification of tumor-initiating cells with stem-like properties in diverse human cancers including GBM represents an important conceptual advance in cancer biology with therapeutic implications. However, the factors determining the differential development and radiosensitization of glioma-initiating cells (GICs) remain poorly defined. Here, we report that rapamycin induced differentiation of GICs and increased their sensitivity to radiation by activating autophagy. Transient in vitro exposure to rapamycin and radiation abolished the capacity of transplanted GICs to establish intracerebral GBMs. Most importantly, in vivo combination of rapamycin and radiation effectively blocked the tumor growth and associated mortality that occurs in mice after intracerebral grafting of human GICs. We demonstrate that rapamycin activated their autophagy and triggers the differentiation cascade in GICs isolated from human GBMs. This was followed by a reduction in proliferation, cell viability, clonogenic ability and increased expression of neural differentiation markers after radiation. Our results suggest that autophagy plays an essential role in the regulation of self-renewal, differentiation, tumorigenic potential and radiosensitization of GICs, suggesting autophagy could be a promising therapeutic target in a subset of GBMs. We propose that autophagy defect in GICs contributes to radioresistance of GICs by desensitizing GICs to normal differentiation cues. Activating autophagy may abrogate the resistance of GICs to radiation and could lead to the development of novel therapeutic approaches for the treatment of GBMs.
authors.affiliation: Department of Pharmacology, Medical School, Soochow University, Suzhou, China.
authors.forename: Wenzhuo
authors.initials: W
authors.lastname: Zhuang
authors.forename: Bingzong
authors.initials: B
authors.lastname: Li
authors.forename: Linmei
authors.initials: L
authors.lastname: Long
authors.forename: Liesong
authors.initials: L
authors.lastname: Chen
authors.forename: Qiang
authors.initials: Q
authors.lastname: Huang
authors.forename: Zhongqin
authors.initials: Z
authors.lastname: Liang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001343:Autophagy; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014965:X-Rays
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus